This project is focused on the clinical study of patients with AIDS-related malignancies. Much of the work is focused on tumors associated with Kaposis sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). This virus is the cause of Kaposis sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castlemans disease (MCD). We have hypothesized that interleukin-12 (IL-12) may be usedul against KS based on its anti-angiogenesis activity, its ability to induce thpe-2 T cell immunity, and its induction of inducible factor 10 (IP-10) which in turn downregulates a G protein coupled receptor (GPCR) encoded by KSHV open reading frame (ORF) (ORF74). We have found that IL-12 is active against KS both when used alone and when combined with a liposomal doxorubicin. We are also studying antibody to VEGF (bevacizumab) as a therapeutic agent in KS as well as BAY 43-9007 (sorafineb). This latter agent is of interest because it can downregulate several receptors for VEGF. We have also initiated a trial of bevacizumab in combination with liposomal doxorubicin in patients with severe KS. We have initiated a clinical trial to study the natural history of MCD and to explore the treatment of MCD using a combination of AZT and valganciclovir, a pro-drug of ganciclovir as well as several other approaches (including liposomal doxorubicin and rituxuimab). In addition, we are studying other patients with KSHV infection to assess factors that may be linked to malignancy. We are exploring methotrexate-based therapy for primary central nervous system lymphoma (PCNSL). We are also studying infusional chemotherapy as therapy for AIDS-associated lymphoma in collaboration with the Metabolism Branch.